Purpose: :
To understand the pathogenesis of Best vitelliform macular dystrophy(BVMD) and other diseases caused by mutations in the gene BEST1encoding the protein bestrophin-1 (Best1).

Methods: :
Knock-in mice carrying the mutation W93C in Best1 were generated.Mice were examined using conventional electroretinography (ERG)to follow rod and cone function. RPE generated ERG responseswere recorded by dc-ERG. Histopathology was examined in miceup to 2 years of age. Changes in Ca2+ and pH were determinedusing the fluorescent reporters fura-2 and SNARF-1 respectively.

Results: :
No differences in scotopic or photopic ERG responses were observedin Best1 knock-in mice compared to wild type. However, dc-ERGrecordings revealed significant differences primarily in theLP component that was enhanced at low stimulus intensities andreduced in the middle of the intensity range (-1.0 to +1.0 logcd/m2) in Best1+/ki and Best1ki/ki mice. As a result, therewas no modulation of LP amplitude across a 2-log unit intensityrange where the wild type response demonstrates a marked increase.Neither Best1+/ki mice nor Best1ki/ki mice exhibited a maximumLP amplitude that was significantly diminished with respectto their wild type littermates. Postmortem analysis identifiedan increase in lipofuscin accumulation in the RPE of Best1+/kiand Best1ki/ki mice by 2 years of age. Examination of RPE explantsidentified changes in pH homeostasis and inhibition of the ATP-stimulatedrelease of intracellular Ca2+ stores.

Conclusions: :
We conclude from this data that Best1+/ki and Best1ki/ki micereproduce two key features of BVMD: a diminished EOG LP andlipofuscin accumulation in the RPE. Importantly this phenotypeis associated with functional deficits in pH homeostasis andCa2+ signaling, implying that BVMD does not result from a lossof Best1 Cl- channel activity, but a more general dysfunctionin ion transport and homeostasis.